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Lung cancer (LC) is one of the top ten malignant tumors and the first leading cause of cancer-related death among both men and women worldwide. It is imperative to identify immune-related biomarkers for early LC diagnosis and treatment. Three Gene Expression Omnibus (GEO) datasets were selected to acquire the differentially expressed genes(DEGs) between LC and normal lung samples through GEO2R tools of NCBI. To identify hub genes, the DEGs were performed functional enrichment analysis, the protein-protein interaction (PPI) network construction, and Lasso regression. Then, a nomogram was constructed to predict the prognosis of patients with carcinoma based on hub genes. We further evaluated the influence of COL1A1 on clinical prognosis using GSE3141, GSE31210, and TCGA database. Also, the correlations between COL1A1 and cancer immune infiltrates and the B7-CD28 family was investigated via TIMER and GEPIA. Further analysis of immunohistochemistry shown that the COL1A1 expression level is positively correlated with CD276 expression level. By difference analysis, there were 340 DEGs between LC and normal lung samples. Then, we picked out seven hub genes, which were identified as components of the risk signature to divide LC into low and high-risk groups. Among them, the expression of COL1A1 is highly correlated with overall survival(OS) and progression-free survival (PFS) (  < 0.05). Importantly, there is a moderate to strong positive relationships between COL1A1 expression level and infiltration level of CD4+ T cells, Macrophage, Neutrophil, and Dendritic cell, as well as CD276 expression level. These findings suggest that COL1A1 is correlated with prognosis and immune infiltrating levels, including CD4+ T cells, Macrophage, Neutrophil, and Dendritic cell, as well as CD276 expression level, indicating COL1A1 can be a potential immunity-related biomarker and therapeutic target in LC.

Hypoxia mediates a metabolic switch from oxidative phosphorylation to glycolysis and increases glycogen synthesis. We previously found that glycogen branching enzyme (GBE1) is downstream of the hypoxia-inducible factor-1 (HIF1) signaling pathway in lung adenocarcinoma (LUAD) cells; however, the molecular mechanism underlying HIF1 regulation of GBE1 expression remains unknown. Herein, the effect of GBE1 on tumor progression via changes in metabolic signaling under hypoxia in vitro and in vivo was evaluated, and GBE1-related genes from human specimens and data sets were analyzed. Hypoxia induced GBE1 upregulation in LUAD cells. GBE1-knockdown A549 cells showed impaired cell proliferation, clone formation, cell migration and invasion, angiogenesis, tumor growth, and metastasis. GBE1 mediated the metabolic reprogramming of LUAD cells. The expression of gluconeogenesis pathway molecules, especially fructose-1,6-bisphosphatase (FBP1), was markedly higher in shGBE1 A549 cells than it was in the control cells. FBP1 inhibited the tumor progression of LUAD. GBE1-mediated FBP1 suppression via promoter methylation enhanced HIF1α levels through NF-κB signaling. GBE1 may be a negative prognostic biomarker for LUAD patients. Altogether, hypoxia-induced HIF1α mediated GBE1 upregulation, suppressing FBP1 expression by promoter methylation via NF-κB signaling in LUAD cells. FBP1 blockade upregulated HIF1α, triggered the switch to anaerobic glycolysis, and enhanced glucose uptake. Therefore, targeting HIF1α/GBE1/NF-κB/FBP1 signaling may be a potential therapeutic strategy for LUAD.

Background Current evidence underlines the active role of neural infiltration and axonogenesis within the tumor microenvironment (TME), with implications for tumor progression. Infiltrating nerves stimulate tumor growth and dissemination by secreting neurotransmitters, whereas tumor cells influence nerve growth and differentiation through complex interactions, promoting tumor progression. However, the role of neural infiltration in the progression of non-small cell lung cancer (NSCLC) remains unclear. Methods This study employs the techniques of immunohistochemistry, immunofluorescence, RNA sequencing, molecular biology experiments, and a murine orthotopic lung cancer model to deeply analyze the specific mechanisms behind the differential efficacy of NSCLC immunotherapy from the perspectives of neuro-tumor signal transduction, tumor metabolism, and tumor immunity. Results This study demonstrates that nerve growth factor (NGF) drives neural infiltration in NSCLC, and 5-hydroxytryptamine (5-HT), which is secreted by nerves, is significantly elevated in tumors with extensive neural infiltration. Transcriptome sequencing revealed that 5-HT enhanced glycolysis in NSCLC cells. Pathway analysis indicated that 5-HT activated the PI3K/Akt/mTOR pathway, promoting tumor metabolic reprogramming. This reprogramming exacerbated immunosuppression in the TME. Neutralizing 5-HT-mediated metabolic reprogramming in tumor immunity enhanced the efficacy of PD-1 monoclonal antibody treatment in mice. Conclusions The findings of this study provide a novel perspective on the crosstalk between nerves and lung cancer cells and provide insights into further investigations into the role of nerve infiltration in NSCLC progression.

The deubiquitinating enzyme USP1 (ubiquitin-specific protease 1) plays a role in the progression of various tumors, emerging as a potential therapeutic target. This study aimed to determine the role of USP1 as a therapeutic target in hepatocellular carcinoma (HCC). We detected USP1 expression in the tumor and adjacent tissues of patients with HCC using immunohistochemical staining. We evaluated the effect of the USP1 inhibitor ML-323 on HCC cell proliferation and cell cycle using a CCK-8 cell-counting kit and plate cloning assays, and propidium iodide, respectively. Apoptosis was detected by annexin V-FITC/Propidium Iodide (PI) staining and caspase 3 (casp3) activity. Transmission electron microscopy and LC3B immunofluorescence were used to detect autophagy. Western blotting was used to detect the accumulation of ubiquitinated proteins, the expression of endoplasmic reticulum (ER) stress-related proteins, and the AMPK-ULK1/ATG13 signaling pathway. We demonstrated that ML-323 inhibits the growth of HCC cells and induces G1 phase cell cycle arrest by regulating cyclin expression. ML-323 treatment resulted in the accumulation of ubiquitinated proteins, induced ER stress, and triggered Noxa-dependent apoptosis, which was regulated by the Activating Transcription Factor 4(ATF4). Moreover, active ER stress induces protective autophagy by increasing AMPK phosphorylation; therefore, we inhibited ER stress using 4-Phenylbutyric acid (4-PBA), which resulted in ER stress reduction, apoptosis, and autophagy in ML-323-treated HCC cells. In addition, blocking autophagy using the AMPK inhibitor compound C (CC), chloroquine (CQ), or bafilomycin A1 (BafA1) enhanced the cytotoxic effect of ML-323. Our findings revealed that targeting USP1 may be a potential strategy for the treatment of HCC.

Background Changes in glycogen metabolism is an essential feature among the various metabolic adaptations used by cancer cells to adjust to the conditions imposed by the tumor microenvironment. Our previous study showed that glycogen branching enzyme (GBE1) is downstream of the HIF1 pathway in hypoxia-conditioned lung cancer cells. In the present study, we investigated whether GBE1 is involved in the immune regulation of the tumor microenvironment in lung adenocarcinoma (LUAD). Methods We used RNA-sequencing analysis and the multiplex assay to determine changes in GBE1 knockdown cells. The role of GBE1 in LUAD was evaluated both in vitro and in vivo. Results GBE1 knockdown increased the expression of chemokines CCL5 and CXCL10 in A549 cells. CD8 expression correlated positively with CCL5 and CXCL10 expression in LUAD. The supernatants from the GBE1 knockdown cells increased recruitment of CD8 + T lymphocytes. However, the neutralizing antibodies of CCL5 or CXCL10 significantly inhibited cell migration induced by shGBE1 cell supernatants. STING/IFN-I pathway mediated the effect of GBE1 knockdown for CCL5 and CXCL10 upregulation. Moreover, PD-L1 increased significantly in shGBE1 A549 cells compared to those in control cells. Additionally, in LUAD tumor tissues, a negative link between PD-L1 and GBE1 was observed. Lastly, blockade of GBE1 signaling combined with anti-PD-L1 antibody significantly inhibited tumor growth in vivo. Conclusions GBE1 blockade promotes the secretion of CCL5 and CXCL10 to recruit CD8 + T lymphocytes to the tumor microenvironment via the IFN-I/STING signaling pathway, accompanied by upregulation of PD-L1 in LUAD cells, suggesting that GBE1 could be a promising target for achieving tumor regression through cancer immunotherapy in LUAD.

Background Recent studies have reported that microRNAs (miRNAs) often function as negative post-transcriptional regulators with altered expression levels found in colorectal cancer (CRC). There have been few studies on miRNAs that regulate the oncogenic alterations in CRC. Here, we aim to explore the anti-cancer miRNA and the potential mechanisms by which miRNAs modulate CRC progression. Methods We performed an integrated analysis of CRC miRNA expression datasets in The Cancer Genome Atlas (TCGA). The miRNA with the lowest expression, miR-760, was validated in an independent validation sample cohort of 76 CRC tissues. Functional assays, such as CCK-8 assay, colony formation assay, and CFSE staining, were used to determine the oncogenic role of miR-760 in human CRC progression. Furthermore, western blotting and dual-luciferase reporter assay were used to determine the mechanism by which miR-760 promotes proliferation of CRC cells. Xenograft nude mouse models were used to determine the role of miR-760 in CRC tumorigenicity in vivo. Immunohistochemical assays were conducted to study the relationship between miR-760 expression and basic leucine zipper transcriptional factor ATF-like 3 (BATF3) expression in human CRC samples. Results miR-760 was markedly downregulated in CRC tissues, and low miR-760 expression was associated with poor prognosis among CRC patients. Upregulation of miR-760 suppressed CRC cell proliferation, whereas downregulation of miR-760 promoted CRC proliferation in vitro. Additionally, we identified BATF3 as a direct target of miR-760, and that the essential biological function of miR-760 during CRC progression both in vitro and in vivo is to suppress the expression of BATF3 and downstream cyclinD1 via AP-1 transcription factor. Finally, we showed a significant correlation between miR-760 and BATF3 expression in CRC tissues. Conclusions miR-760 inhibited CRC growth by downregulating BATF3/AP-1/ cyclinD1 signaling.

Diffuse large B cell lymphoma (DLBCL) is one of the most usual types of adult lymphoma with heterogeneousness in histological morphology, prognosis, and clinical indications. Prior to this, several studies were carried out to determine the DLBCL subtype based on the analysis of the genome profile. However, classification based on assessment of genes related to the immune system has limited clinical significance for DLBCL. We systematically explored the DLBCL gene expression dataset and provided publicly available clinical information on patients with GEO. In this research, 928 DLBCL samples were applied, and we calculated 29 immune-related genomes’ enrichment levels in each sample and stratified them into high immunity (Immunity_H, n=135, 28.7%), moderate immunity (Immunity_M, n=135, 28.7%), and low immunity (Immunity_L, n=12, 2.6%) that was based on ssGSEA score. The ESTIMATE algorithm was used to calculate stromal scores (range 586.88 to 1982.43), immune scores, estimated scores (range 2,618.2 to 8,098.14), and tumor purity (range 0.216 to 0.976). All of them were significantly correlated with immune subtypes (Kruskal-Wallis test, p<0.001). At the same time, the correlation of related genes was analyzed by immunohistochemistry staining. In addition, DLBCL cells were cultured in transfected and in vitro with siRNA to verify correlation analysis and gene expression. Finally, human peripheral blood lymphocytes were incubated with DLBCL cells and stained. Flow cytometry was applied to analyze genes’ influence on immune function. By analysis, immune checkpoint and HLA gene expression levels were higher in the Immunity_H group (Kruskal-Wallis test, p<0.05). The levels of Tfhs (follicular helper T cells), monocytes, CD8+ T cells, M1 macrophages, M2 macrophages, and CD4+ memory-activated T cells were the most excellent in Immunity_H, and the total survival rate was higher in the Immunity_L. Through analysis, IRF4 (MUM1) was identified by us as immunotherapeutic target and a potential prognostic marker for DLBCL, which was made sure by using molecular biology experimentations. To conclude, immunosignature made a connection between DLBCL subtypes playing a position in DLBCL prognostic stratification. Immunocharacteristics-related DLBCL subtypes’ construction predicts expected patient results and supplies conceivable immunotherapy candida.

BackgroundImproving the efficacy of anti-programmed death 1 (PD-1) monoclonal antibody (mAb) therapy remains a major challenge for cancer immunotherapy in non-small cell lung cancer (NSCLC). Gut microbial metabolites can influence immunotherapy efficacy.MethodsELISA was used to compare the serum 5-hydroxyindoleacetic acid (5-HIAA) level in patients with NSCLC. Humanized mice were constructed to observe the effect of 5-HIAA on immunotherapy. RNA-seq and flow cytometry were used to analyze the effect of 5-HIAA on tumor-infiltrating lymphocytes. The effects of phenelzine (Phe) and Akkermansia muciniphila (AKK) on 5-HIAA synthesis, antitumor immunity and immunotherapy efficacy were analyzed. Finally, the synergistic effect of Phe combined with AKK on anti-PD-1 mAb was observed.ResultsHere we found that 5-HIAA, which is regulated by gut microbiota, has increased concentrations in the serum of non-responders to immunotherapy. Supplementation of 5-HIAA inhibited the efficacy of anti-PD-1 mAb and tumor infiltration of CD8+ T cells. The use of monoamine oxidase inhibitor (MAO-I) Phe inhibited the synthesis of 5-HIAA, then improved the efficacy of anti-PD-1 mAb. In addition, supplementation of AKK can also decrease 5-HIAA in serum. Finally, the combination of Phe and AKK maximally inhibited 5-HIAA synthesis and improved immunotherapy efficacy.ConclusionsOur investigations reveal that alterations in gut microbial composition leading to increased 5-HIAA synthesis can negatively impact CD8+ T cell functionality and the success of immunotherapy. The combination of Phe and AKK supplementation holds potential for optimizing immunotherapy efficacy.

The 5-methylcytosine (m5C) is one of the important forms of RNA post modification, and its regulatory mechanism in tumors has received increasing attention. However, its potential role in colorectal cancer remains unclear. Here, we systematically investigated the genetic variation and prognostic value of the 14 m5c RNA methylation regulators in colon cancer. The prognostic risk score was constructed using three m5C regulators, which was verified in the GSE17536 (N=177), GSE41258 (N=248) and GSE38832 (N=122) datasets. The risk score developed from the three-m5C signature represents an independent prognostic factor, which can accurately predict the prognosis of patients with colon cancer in multiple datasets. The cytokine-cytokine receptor interaction and chemokine signaling pathway were significantly enriched in the low-risk score group. Further analysis showed that the three-m5C signature was related to tumor immune microenvironment (TIME), affecting the abundance of tumor-infiltrating immune cells. Especially, patients with low risk score had higher immune score than those with high risk score. In addition, gene set enrichment analysis (GSEA) confirmed that all three regulatory factors are associated with the MAPK/p38 signaling pathway. In conclusion, our study illustrates that the three-m5C signature may be involved in the regulation of colon cancer immune microenvironment in synergy with the MAPK signaling pathway. Therefore, further studying the three-m5C signature regulatory mechanisms might provide promising targets for improving the responsiveness of colon cancer to immunotherapy.

Background Hepatocyte growth factor (HGF) binds to the c-mesenchymal-epithelial transition (C-MET) receptor and activates downstream signaling pathways, playing an essential role in the development of various cancers. Given the role of this signaling pathway, the primary therapeutic direction focuses on identifying and designing HGF inhibitors, antagonists and other molecules to block the binding of HGF to C-MET, thereby limiting the abnormal state of other downstream genes. Methods This study focuses on the analysis of immune-related genes and corresponding immune functions that are significantly associated with the HGF/c-MET pathway using transcriptome data from 11 solid tumors. Results We systematically analyzed 11 different cancers, including expression correlation, immune infiltration, tumor diagnosis and survival prognosis from HGF/c-MET pathway and immune regulation, two biological mechanisms having received extensive attention in cancer analysis. Conclusion We found that the HGF/c-MET pathway affected the tumor microenvironment mainly by interfering with expression levels of other genes. Immune infiltration is another critical factor involved in changes to the tumor microenvironment. The downstream immune-related genes activated by the HGF/c-MET pathway regulate immune-related pathways, which in turn affect the degree of infiltration of immune cells. Immune infiltration is significantly associated with cancer development and prognosis.